α-Melanocyte Stimulating Hormone Prevents GABAergic Loss and Improves Cognitive Function in Alzheimer's Disease

In Alzheimer's disease (AD), the appropriate excitatory/inhibitory balance required for memory formation is impaired. In order to elucidate deficits in the inhibitory gamma-aminobutyric acid (GABA)-ergic system in AD and to establish a link between GABAergic dysfunction and cognition, the TgCRND8 mouse model of AD was utilized. TgCRND8 mice with established amyloid beta peptide (Abeta) pathology exhibit spatial memory deficits and altered anxiety. Concomitant with behavioural changes, GABAergic deficits are observed in the hippocampus. The GABAergic marker glutamic acid decarboxylase 67 (GAD67) mRNA and protein levels in the hippocampus as well as the number of GAD67+ GABAergic cells in the CA1 region of the hippocampus are significantly decreased. However, at this stage of Abeta pathology, the number of ChAT+ cholinergic cells in the septum remains unchanged, suggesting that cholinergic cells may not underlie behavioural deficits. The GABAergic loss may represent an early target in AD disease progression. By increasing inhibition, the physiological excitatory/inhibitory balance in the brain may be restored resulting in normal function. I found that the neuropeptide, alpha-melanocyte stimulating hormone (alpha-MSH), prevents the loss of GAD67 mRNA, protein levels and GAD67+ cells in the CA1 region of the hippocampus. In particular, alpha-MSH protects the loss of the somatostatin (SST) expressing subtype of GAD67+ inhibitory interneurons. SST is reduced in the CSF and brain of AD patients and SST levels are correlated with cognitive function. By preserving hippocampal GAD67+ cells, especially the SST+ subtype, alpha-MSH improved spatial memory in TgCRND8 mice and prevented changes in anxiety independent of altering Abeta; peptide load in the brain. alpha-MSH modulated the excitatory/inhibitory balance in the brain by restoring GABAergic inhibition and as a result, improved cognition in TgCRND8 mice.Ph.D.2016-11-30 00:00:0